Investigators Seek Explanations for Exercise Intolerance for Sickle Cell Patients


The main mechanism for exercise intolerance is impaired blood oxygen carrying capacity.

New research explains why patients with sickle cell anemia (SCA) commonly suffer from exercise intolerance, 1 of the most frequent complaints for this patient population.

A team, led by Nadjib Hammoudi, Sorbonne Université, ACTION Study Group, INSERM, UMR_S 1166, Institute of Cardiometabolism And Nutrition (ICAN), Hôpital Pitié-Salpêtrière (AP-HP), Boulevard de l'hôpital, investigated exercise cardiovascular reserve as a potential contributor of exercise intolerance in adult patients with SCA.


The complex, underlying mechanisms of exercise intolerance in patients with sickle cell anemia remains unknown, with most previous studies assessing cardiac function at rest and not latent heart failure at rest, which could be unmasked by exercise.

While treatment has improved conditions for patients with sickle cell anemia, exercise intolerance has remained a frequent complaint that becomes worse as the patient ages.

“The main mechanism underlying this exercise intolerance is impaired blood oxygen carrying capacity due to chronic anemia,” the authors wrote. “Another is altered pulmonary vasculature as a consequence of chronic hemolysis and repetitive pulmonary vascular obstruction episodes.”

The Study

In the observational, prospective study, the investigators compared 60 patients with sickle cell anemia with a health control group of 20 matched participants. The median age of the sickle cell cohort was 31 years old and 60% of the patients were women.

Each participant underwent symptom-limited combined exercise echocardiography and oxygen uptake (VO2) measurements. The team calculated the differences between arterial and venous oxygen content (C(a-v)O2).

Cardiac reserve was defined as the absolute change in cardiac index from baseline to peak exercise and the investigators recorded resting left atrial maximal at the end of the LV systole using the biplane Simpson method. This was indexed to body surface area.

Each patient exercised at maximal intensity until exhaustion, which was indicated by the Borg score and a median value of peak respiratory exchange ratio above 1.2.


Exercise capacity was severely reduced in patients with sickle cell anemia, shown by a 43% decrease in peak VO­­2 and a 48% reduction in workload. Also, the first ventilatory threshold was reached at a lower workload.

Patients with sickle cell anemia were more likely than the control group to exhibit severe exercise intolerance (median peakVO2, 34.3 vs 19.7ml/min/kg respectively, P <0.0001) and displayed heterogeneously increased cardiac index from rest to peak exercise (median +5.8, range 2.6-10.6L/min/m²). This correlated with peak VO2 (r = 0.71; P <0.0001).

On the other hand, the C(a-v)O2 exercise reserve was homogenously reduced and did not correlate with peakVO2 (r = 0.18, P = 0.16).

The patients only displayed mild pulmonary function impairment, which was not linked to exercise capacity and pulse oximetry was not modified during exercise (99 [98 – 100] % both at baseline and peak exercise, P = 0.10) and there was no evidence of mechanical ventilatory limitation during exercise.

In addition, hemoglobin levels and C(a-v)O2 were similar in different subgroups of patients with sickle cell anemia, but these patients in the lower VO2 tertial had chronotropic incompetence and left ventricular diastolic dysfunction—left atrial peak longitudinal strain was reduced and both E/e’ ratio and left atrial volume index were increased.

These patients were charactered by a reduced cardiac reserve.

“Altered cardiac reserve due to chronotropic incompetence and left ventricular diastolic dysfunction seems to be an important determinant of exercise intolerance in adult SCA patients,” the authors wrote.

The study, “Altered cardiac reserve is a determinant of exercise intolerance in sickle cell anemia patients,” was published online in the European Journal of Clinical Investigation.

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